Preventive or Therapeutic Drug for Alzheimer-Type Dementia

ABSTRACT

It is intended to provide a highly safe preventive or therapeutic drug for Alzheimer-type dementia which can replace the conventional therapies currently used for Alzheimer-type dementia or which can be used together with the conventional therapy to realize high therapeutic effects, characterized in that a ω-3 polyunsaturated fatty acid and thyroid hormone are used in combination.

TECHNICAL FIELD

This invention relates to a novel preventive or therapeutic drug forAlzheimer-type dementia, and more specifically, to a preventive ortherapeutic drug for Alzheimer-type dementia wherein an ω-3polyunsaturated fatty acid is used in combination with a thyroidhormone.

BACKGROUND ART

With the progress of aging of the society, number of patients sufferingfrom dementia is ever more increasing. Dementia is the condition inwhich acquired intelligence has persistently declined by organicdisorder of brain. Dementia has been classified into several types basedon the pathogenesis and histopathology, and the most typical types areAlzheimer-type dementia and cerebrovascular dementia. Conceivably, thesetwo types of dementia and the mixed type of these two constitute 80 to90% of the entire dementia case.

Alzheimer-type dementia is associated with atrophy of brain, and up tothis moment, no drug has been found that can fundamentally treat thisdisease. The only commercially available pharmaceutical product with theindication for Alzheimer-type dementia is donepezil hydrochloride (tradename Aricept: manufactured by Eisai Co., Ltd.). This product, however,is indicated for “inhibition of the advance of dementia symptoms ofslight or moderate Alzheimer-type dementia”, and this product may not besufficient in view of fundamental treatment of the disease.

Icosapentaenoic acid (also referred to as eicosapentaenoic acid,hereinafter abbreviated as EPA) which is a member of ω-3 polyunsaturatedfatty acids is a polyunsaturated fatty acid extracted and purified fromfish oil, and EPA is known for its effect of reducing serum lipids,suppressing platelet aggregation, and the like. In Japan, ethyl ester ofthis EPA is commercially available as a therapeutic drug forarteriosclerosis obliterans and a therapeutic drug for hyperlipidemia.EPA has been reported to retard advance of symptoms of Alzheimer-typedementia (see, for example, Non-patent document 1). This documentdiscloses that, when the patients suffering from Alzheimer-type dementiawere administered with EPA at a daily dose of 900 mg for 12 months, andthe symptoms were observed (number of the evaluated case: 22),“administration of EPA to the patients of Alzheimer-type dementiaresulted in the improvement of the cognitive skill for 3 to 6 months.However, after this period, the cognitive skill declined with thenatural prognosis of the disease” (page 27, right column).

This document, however, does not disclose or indicate excellent effectson the Alzheimer-type dementia achieved by the combination of the ω-3polyunsaturated fatty acid and thyroid hormone.

[Non-patent document]

Dementia Japan, 2001, vol. 15, pp. 21-29.

DISCLOSURE OF THE INVENTION

In view of the situation as described above, an object of the presentinvention is to provide a highly safe preventive or therapeutic drug forAlzheimer-type dementia which can replace the conventional therapiescurrently used for Alzheimer-type dementia or which can be used togetherwith the conventional therapy to realize high therapeutic effects.

The inventors of the present invention carried out an intensive study onthe preventive or therapeutic drug for Alzheimer-type dementia, andfound that use of a combination of an ω-3 polyunsaturated fatty acid anda thyroid hormone exhibits excellent therapeutic effects forAlzheimer-type dementia as well as high safety. The present inventionhas been completed on the basis of such finding.

The preventive or therapeutic drug for Alzheimer-type dementia whereinan ω-3 polyunsaturated fatty acid is used in combination with a thyroidhormone has significant therapeutic effects for the Alzheimer-typedementia while it exhibits no adverse events, and accordingly, it shouldprovide a highly effective preventive or therapeutic drug forAlzheimer-type dementia with high safety.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention is described in detail.

According to an aspect of the present invention, the present inventionprovides a preventive or therapeutic drug for Alzheimer-type dementiawherein an ω-3 polyunsaturated fatty acid is used in combination with athyroid hormone.

According to another aspect of the present invention, the presentinvention provides a food having a preventive or therapeutic effect forAlzheimer-type dementia wherein an ω-3 polyunsaturated fatty acid isused in combination with a thyroid hormone.

A polyunsaturated fatty acid is defined as a fatty acid having two ormore carbon-carbon double bonds in the molecule, and the polyunsaturatedfatty acids are further grouped by the position of the double bond intoω-3, ω-6, and other polyunsaturated fatty acids. Exemplary ω-3polyunsaturated fatty acids include α-linolenic acid, EPA, anddocosahexaenoic acid (hereinafter abbreviated as DHA). Thepolyunsaturated fatty acid used in the present invention may be either asynthetic or a natural polyunsaturated fatty acid, or a natural oilcontaining such polyunsaturated fatty acids. Synthetic products includethose which have been produced by chemical synthesis, and semi-syntheticproducts which have been produced by microorganisms and then subjectedto esterification, ester exchange, or the like. The natural products maybe either those extracted from a natural oil containing polyunsaturatedfatty acids by a known means or those which have been further processedto produce a crude product or further purified products. Salts of an ω-3polyunsaturated fatty acid as well as derivatives such as ester, amide,phospholipid, monoglyceride, diglyceride, and triglyceride of apolyunsaturated fatty acid are also included within the ω-3polyunsaturated fatty acid used in the present invention.

The ω-3 polyunsaturated fatty acid used in the present invention ispreferably at least one member selected from EPA, DHA, and α-linolenicacid. Still more preferably, the ω-3 polyunsaturated fatty acid is EPA,DHA, or a mixture thereof, and even more preferably, the ω-3polyunsaturated fatty acid is ethyl icosapentate (hereinafterabbreviated as EPA-E), ethyl docosahexaenoate (hereinafter abbreviatedas DHA-E), or a mixture thereof. Most preferably, the ω-3polyunsaturated fatty acid is EPA-E. In Japan, a soft capsulepreparation containing high purity EPA-E (trade name Epadel,manufactured by MOCHIDA PHARMACEUTICAL CO., LTD.) is commerciallyavailable as a therapeutic drug for arteriosclerosis obliterans (ASO) orhyperlipidemia, and this product can be used. An example of the mixtureof EPA-E and DHA-E is Omacor (a soft capsule containing about 46% byweight of EPA-E and about 38% by weight of DHA-E manufactured by RossProducts), which is commercially available in the U.S. and the like as atherapeutic agent for hypertriglyceridemia, and which may be used in thepresent invention. Also preferred are the embodiments wherein the ω-3polyunsaturated fatty acid is in the form of a purified fish oil as wellas the embodiments wherein the ω-3 polyunsaturated fatty acid is atleast one member selected from monoglyceride, diglyceride, andtriglyceride.

The purity of the ω-3 polyunsaturated fatty acid used in the compositionof the present invention, namely, content of the ω-3 polyunsaturatedfatty acid in the entire fatty acid is not particularly limited.However, the purity is preferably at least 25% by weight, morepreferably at least 50% by weight, still more preferably at least 70% byweight, and still more preferably at least 85% by weight, and mostpreferably, the purity of the polyunsaturated fatty acid is such that itis substantially free from fatty acid components other than the ω-3polyunsaturated fatty acid.

ω-3 polyunsaturated fatty acid is easily oxidized, and therefore,simultaneous incorporation of an effective amount of an antioxidant suchas butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate,gallic acid, a pharmaceutically acceptable quinone, or α-tocopherol isdesirable.

The thyroid hormone used in the present invention is not particularlylimited as long as it exhibits the effects intended in the presentinvention. Exemplary thyroid hormones include levothyroxine andliothyronine, and the preferred is levothyroxine sodium (trade name,Thyradin S, manufactured by ASKA Pharmaceutical Co., Ltd.). It is to benoted that substantially same effects are realized by using a growthhormone (for example, somatropin) instead of the thyroid hormone.

The preventive or therapeutic drug for Alzheimer-type dementia of thepresent invention may be administered either by solely administering theeffective components (possibly with other inevitable componentsremaining after the purification), or by forming an adequatepharmaceutical preparation with a carrier or a medium commonly used inthe art such as an excipient, a binder, a lubricant, a colorant, or aflavor, optionally with sterilized water or a vegetable oil, or furtherwith a non-toxic organic solvent or a non-toxic solubilizer (forexample, glycerin or propylene glycol), an emulsifier, a suspendingagent (for example, Tween 80 and or arabic solution), an isotonic agent,a pH adjusting agent, a stabilizer, a soothing agent. The food having apreventive or therapeutic effects for Alzheimer-type dementia of thepresent invention may also be prepared either with solely the effectivecomponent (possibly with other inevitable components remaining after thepurification), or in combining with a carrier or a medium commonly usedin the art as in the case of the preventive or therapeutic drug forAlzheimer-type dementia. Exemplary preferable foods include supplement,nutraceutical, food with nutrient function claims, food for specifiedhealth uses, and health food.

The pharmaceutical preparation may be administered orally,intravenously, intraarterially, by inhalation, endorectally,intravaginally, or externally in the dosage form of a tablet, a capsule,a microcapsule, granules, fine granules, a powder, an oral liquid, asuppository, a syrup, an inhalant, an ointment, an injection (emulsion,suspension, or non-aqueous), or an injection in the form of emulsion orsuspension which has been prepared from a solid injection immediatelybefore the administration. The preferred is the oral administration byencapsulating in a capsule such as a soft capsule or a microcapsule.Also preferred is intravenous or intraarterial administration in theform of an injection (emulsion, suspension, or non-aqueous) or aninjection in the form of emulsion or suspension which has been preparedfrom a solid injection immediately before the administration.

The dose of the ω-3 polyunsaturated fatty acid of the preventive ortherapeutic drug for Alzheimer-type dementia of the present inventionmay be an effective amount to exhibit the intended behavior which may beadequately adjusted by the dosage form, administration route, frequencyof administration per day, seriousness of the symptom, body weight, age,and the like. When ethyl icosapentate is orally administered, a dose interms of EPA-E is typically 100 to 9,000 mg/day, preferably 300 to 6,000mg/day, and more preferably 300 to 2,700 mg/day which may beadministered in 2 to 3 divided doses, or if desired in a single dose orin several divided doses.

The dose of the thyroid hormone of the preventive or therapeutic drugfor Alzheimer-type dementia of the present invention may be an effectiveamount to exhibit the intended behavior which may be adequately adjustedby the dosage form, administration route, frequency of administrationper day, seriousness of the symptom, body weight, age, and the like.When levothyroxine sodium is orally administered, a dose in terms oflevothyroxine sodium of 25 to 200 μg/day may be administered once a day.Such dose, however, may be administered in several divided doses.

The combination of the daily dose of the EPA-E and the daily dose of thelevothyroxine sodium is not particularly limited. However, thiscombination is preferably one of (1) 1,800 to 2,700 mg/day of EPA-E and25 to 200 μg/day of levothyroxine sodium, (2) 1,800 to 2,700 mg/day ofEPA-E and 25 to 100 μg/day of levothyroxine sodium, (3) 300 to 600mg/day of EPA-E and 25 to 200 μg/day of levothyroxine sodium, and (4)300 to 600 mg/day of EPA-E and 25 to 100 μg/day of levothyroxine sodium.

The a preventive or therapeutic drug for Alzheimer-type dementia of thepresent invention characterized by the combined use of an ω-3polyunsaturated fatty acid and a thyroid hormone may be in the formof 1) combined taking of the both drugs, namely, simultaneous orseparate taking of the drug containing the ω-3 polyunsaturated fattyacid and the drug containing the thyroid hormone; 2) a combined drug,namely, a drug prepared by incorporating both of the ω-3 polyunsaturatedfatty acid and the thyroid hormone, and 3) a kit containing both drugs,namely, a set prepared by combining a unit dose (single dose, dailydose, etc.) of the drug containing an ω-3 polyunsaturated fatty acid andthe drug containing a thyroid hormone. The preventive or therapeuticdrug for Alzheimer-type dementia of the present invention include thedrug containing an ω-3 polyunsaturated fatty acid and a thyroid hormoneas its only effective components, namely, the drug prepared by combiningan ω-3 polyunsaturated fatty acid and a thyroid hormone; and also, apreventive or therapeutic drug for Alzheimer-type dementia furthercomprising an effective component other the ω-3 polyunsaturated fattyacid and the thyroid hormone.

The preventive or therapeutic drug for Alzheimer-type dementia of thepresent invention may be used with any one of the conventionaltherapeutic drug for Alzheimer-type dementia as typically represented bydonepezil (trade name Aricept: manufactured by Eisai Co., Ltd.).Combination with the donepezil enables improvement of the Alzheimer-typedementia whose symptoms could not be sufficiently improved by donepezilalone. Such combination also enables use of the donepezil at a reduceddose.

The preventive or therapeutic drug for Alzheimer-type dementia of thepresent invention wherein an ω-3 polyunsaturated fatty acid is used incombination with a thyroid hormone also includes the case in which apatient of Alzheimer-type dementia who is administered with an ω-3polyunsaturated fatty acid (1) for the purpose of treatinghyperlipidemia or ASO, (2) in the expectation of antiarterioscleroticaction, or (3) in the expectation of preventing onset of thecardiovascular event or cerebrovascular event, and in particular, apatient whose improvement of the symptom of the Alzheimer-type dementiais insufficient is further administered with a thyroid hormone. Alsoincluded in the present invention is the case in which a patient ofAlzheimer-type dementia who is administered with a thyroid hormone, andin particular, a patient whose improvement of the symptom of theAlzheimer-type dementia is insufficient is further administered with adrug containing an ω-3 polyunsaturated fatty acid, and in particular, adrug containing EPA-E.

The severity of the Alzheimer-type dementia to be treated by thetherapeutic drug for Alzheimer-type dementia characterized by the use ofa combination of an ω-3 polyunsaturated fatty acid and a thyroid hormoneof the present invention is not particularly limited. According toReisberg, average score of Hasegawa Dementia Scale (wherein the score ofup to 20 corresponds to “doubt of dementia” on a scale of 30) in eachseverity is such that 19.1 for slight dementia, 15.4 for moderatedementia, 10.7 for slightly advanced dementia, and 4.0 for advanceddementia.

EXAMPLES

Next, the present invention is described in further detail by referringto the Examples, which by no means limit the scope of the presentinvention.

Example Subject and Method

14 patients (6 males and 8 females in their fifties to eighties)diagnosed with Alzheimer-type dementia but having no history of cerebralinfarction and not suffering from primary diseases of dementia such ashypothyroidism were administered with ethyl icosapentate (trade nameEpadel; manufactured by Mochida Pharmaceutical Co., Ltd.; abbreviated as“EPA-E” in the Table) at a daily dose of 300 to 600 mg for 2 months, andthen, also with levothyroxine sodium (trade name thyradin S;manufactured by ASKA Pharmaceutical Co., Ltd.; abbreviated as “T4” inthe Table) at a daily dose of 50 to 100 μg for 4 months in addition tothe ethyl icosapentate. Each patient was evaluated for the improvementof the dementia by Hasegawa Dementia Scale at the start of the test, 2months after the start of the test months from the start ofadministering ethyl icosapentate), and 6 months after the start of thetest (4 months after the start of the combined administration of theethyl icosapentate and the levothyroxine sodium).

[Results]

The results for each case are shown in Table 1. The average score of theHasegawa Dementia Scale is shown in Table 3 together with the averagescore of Reference Examples. As shown in Table 1, when the change insymptoms was observed after the test period of 6 months, improvementssuch as willingness, refection, increase in the habitat, and luciditywere noted. In addition, improvement in the score of Hasegawa DementiaScale was noted in substantially all cases. Average score of theHasegawa Dementia Scale at the start of the test was 10.0, and thisaverage score increased to as high as 16.8 at the end of the test period(6 months after the start of the test). Improvement in the symptoms wasnoted also in somewhat advanced to considerably advanced dementia. Noadverse event was noted.

TABLE 1 Alzheimer-type dementia Hasegawa Dementia Chief Dementia Dose ofDose Scale complaint, history EPA-E of T4 At the After 2 After 6 SideConcomitant Change in No. Gender Age Diagnosis etc. (year) mg/day μg/daystart months months effects drug symptom 1 Female 60′ DementiaForgetfulness 5 300 100 8 9 18 0 None 2 Female 50′ DiabetesForgetfulness 7 600 100 14 14 18 0 Insulin Willingness mellitus,dementia 3 Male 70′ Dementia Forgetfulness 5 600 50 4 7 14 0 None 4Female 60′ Dementia Anorexia 3 300 100 13 14 16 0 None 5 Female 60′Dementia Anorexia 6 600 100 6 8 15 0 None Willingness 6 Female 70′Diabetes Headache 2 600 100 8 11 18 0 SU drug mellitus, dementia 7Female 60′ Diabetes Diabetes 4 600 100 8 11 17 0 Insulin Refectionmellitus, treatment dementia 8 Male 60′ Dementia, Dystropy 1 300 100 1212 14 0 Glucocorti- adrenal coid insuffi- ciency 9 Male 70′ DementiaForgetfulness 7 600 50 16 17 22 0 None Refection 10 Male 60′ DiabetesDiabetes 15 300 100 9 11 14 0 SU drug mellitus, treatment dementia 11Female 70′ Dementia Forgetfulness 5 600 50 10 13 20 0 None Increase inthe habitat 12 Male 80′ Dementia Forgetfulness 5 300 50 11 10 16 0 None13 Female 70′ Hyper- Hypertension 6 600 100 14 15 20 0 Ca Luciditytension, treatment antagonist dementia 14 Male 60′ Diabetes Diabetes 2300 100 7 7 13 0 Insulin Refection mellitus, treatment dementia

Reference Example Subject and Method

10 patients (6 males and 4 females in their fifties to eighties)diagnosed with cerebrovascular dementia but having the history ofcerebral infarction were administered with ethyl icosapentate (tradename Epadel; manufactured by Mochida Pharmaceutical Co., Ltd.;abbreviated as “EPA-E” in the Table) at a daily dose of 300 to 600 mgfor 2 months, and then, also with levothyroxine sodium (trade namethyradin S; manufactured by ASKA Pharmaceutical Co., Ltd.; abbreviatedas “T4” in the Table) at a daily dose of 50 to 100 μg for 4 months inaddition to the ethyl icosapentate. Each patient was evaluated for theimprovement of the dementia by Hasegawa Dementia Scale at the start ofthe test, 2 months after the start of the test (2 months from the startof administering ethyl icosapentate), and 6 months after the start ofthe test (4 months after the start of the combined administration of theethyl icosapentate and the levothyroxine sodium).

[Results]

The results for each case are shown in Table 2. The average score of theHasegawa Dementia Scale is shown in Table 3 together with the averagescore of Examples. As shown in Table 2, average score of the HasegawaDementia Scale was in slightly improving trend in substantially allcases after 6 months although the improvement was not significant. Inthe observation of the symptom, refection was noted in one case (10%).The case that showed such improvement of the symptom was the case inwhich highest score of Hasegawa Dementia Scale had been observed at thestart of the test. No adverse event was noted.

TABLE 2 Cerebrovascular dementia Hasegawa Dementia Chief Dementia Doseof Dose Scale complaint, history EPA-E of T4 At the After 2 After 6 SideConcomitant Change in No. Gender Age Diagnosis etc. (year) mg/day μg/daystart months months effects drug symptom 1 Male 60′ CerebralDisorientation 2 600 100 8 9 11 0 Insulin infarction, diabetes mellitus,dementia 2 Female 60′ Cerebral Paralysis 2 300 100 12 13 14 0 Noneinfarction, dementia 3 Male 50′ Cerebral Slump 1 600 100 14 15 18 0 NoneRefection infarction, dementia 4 Male 60′ Cerebral Forgetfulness 4 600100 10 11 12 0 None infarction, dementia 5 Female 70′ CerebralDisorientation 9 600 50 10 12 14 0 None infarction, dementia 6 Male 60′Cerebral Weight loss 6 300 100 10 10 11 0 Insulin infarction, diabetesmellitus, dementia 7 Female 70′ Cerebral Weight loss 1.5 300 50 11 12 130 None infarction, dementia 8 Female 80′ Cerebral Disorientation 10 30050 9 10 11 0 None infarction, dementia 9 Male 70′ Cerebral Paralysis 5600 50 9 9 13 0 None infarction, dementia 10 Male 60′ Cerebral Insomnia3 600 100 11 11 14 0 SU drug infarction, diabetes mellitus, dementia

TABLE 3 Score of the Hasegawa Dementia Scale (average ± standarddeviation, range) At the 2 months after 6 months after start of thestart of the start of the test the test the test Examples 10.0 ± 3.511.4 ± 3.0 16.8 ± 2.7 (Alzheimer-type (6-16) (7-17) (13-22) dementia)Referential Examples 10.4 ± 1.7 11.2 ± 1.9 13.1 ± 2.1 (Cerebrovascular(9-14) (9-15) (11-18) dementia)

As demonstrated by the results of Table 3, while sole administration ofethyl icosapentate at a dose of 300 to 600 mg/day for 2 months resultedin no substantial change in the scores of the Hasegawa Dementia Scale ofthe patients suffering from Alzheimer-type dementia, simultaneousadministration of levothyroxine sodium for the subsequent 4 months at adose of 50 to 100 μg/day with the ethyl icosapentate resulted in thesignificant improvement in the scores of the Hasegawa Dementia Scale ofthe patients suffering from Alzheimer-type dementia. On the other hand,as demonstrated by the results of the Referential Example in Table 3,only slight improvement in the score of Hasegawa Dementia Scale wasrealized in test of the simultaneous administration of the ethylicosapentate at 300 to 600 mg/day and the levothyroxine sodium at 50 to100 μg/day for the patients of cerebrovascular dementia.

As demonstrated above, the combination of an ω-3 polyunsaturated fattyacid and a thyroid hormone, and in particular, the combination of theEPA-E and the levothyroxine sodium has a significant therapeutic effectsfor Alzheimer-type dementia with no adverse event, and such combinationwould constitute a highly effective and safe preventive or therapeuticdrug for Alzheimer-type dementia. In the meanwhile, since the daily doseof the EPA-E for present indication, namely, hyperlipidemia orarteriosclerosis obliterans (ASO) is 1800 to 2700 mg, the resultsconfirmed that EPA-E exhibits its effect at a dose lower than the usualdose when combined with the levothyroxine sodium. In addition, sinceusual dose (maintenance dose) of the levothyroxine sodium for presentindication is 100 to 400 μg/day, the levothyroxine sodium exhibits wasalso confirmed to exhibit its effect at the lower limit of the usualdose or at an even lower dose.

1. A preventive or therapeutic drug for Alzheimer-type dementia whereinan ω-3 polyunsaturated fatty acid is used in combination with a thyroidhormone.
 2. The preventive or therapeutic drug according to claim 1wherein the ω-3 polyunsaturated fatty acid is icosapentaenoic acid,docosahexaenoic acid, or a mixture of icosapentaenoic acid anddocosahexaenoic acid.
 3. The preventive or therapeutic drug according toclaim 1 wherein the ω-3 polyunsaturated fatty acid is ethylicosapentate, ethyl docosahexaenoate, and a mixture thereof.
 4. Thepreventive or therapeutic drug according to claim 1 wherein the ω-3polyunsaturated fatty acid is ethyl icosapentate.
 5. The preventive ortherapeutic drug according to claim 1 wherein the thyroid hormone islevothyroxine.